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Updated: May 9, 2026
Lipopolysaccharide Infusion as a Porcine Endotoxemic Shock Model
Published on: December 8, 2023
Targeting dexamethasone to macrophages in a porcine endotoxemic model
Asger Granfeldt1, Christine Lodberg Hvas, Jonas Heilskov Graversen
11Department of Anesthesiology, Aarhus University HospitalAarhusDenmark. 2Cytoguide ApS, Incuba Science ParkAarhusDenmark. 3Department of Clinical Biochemistry, Aarhus University HospitalAarhusDenmark. 4Department of Biomedicine, University of AarhusAarhusDenmark.
Objectives:
Macrophages are important cells in immunity and the main producers of pro-inflammatory cytokines. The main objective was to evaluate if specific delivery of glucocorticoid to the macrophage receptor CD163 is superior to systemic glucocorticoid therapy in dampening the cytokine response to lipopolysaccharide infusion in pigs.
Design:
Two randomized, placebo-controlled trials.
Setting:
University hospital laboratory.
Subjects:
Female farm-bred pigs (26-31 kg).
Design:
A humanized antibody that binds to pig and human CD163 was produced, characterized, and conjugated with dexamethasone. In the first study (total n = 12), pigs were randomly assigned to four groups: 1) saline; 2) dexamethasone (1.0 mg/kg); 3) dexamethasone (0.02 mg/kg); and 4) anti-CD163-conjugated dexamethasone (0.02 mg/kg). In the second study (total n = 36), two additional groups were included in addition to the four original groups: 5) anti-CD163-conjugated dexamethasone (0.005 mg/kg); 6) unconjugated anti-CD163. Treatments were given 20 hours prior to infusion of lipopolysaccharide (1 µg × kg × h) for 5 hours. Blood samples were analyzed for cytokines, cortisol, and adrenocorticotropic hormone.
Results:
In the saline group, lipopolysaccharide increased cytokine and plasma cortisol levels. In both studies, dexamethasone (1 mg/kg) and anti-CD163 dexamethasone (0.02 mg/kg) uniformly attenuated tumor necrosis factor-α peak levels (both p < 0.05) compared with low-dose dexamethasone (0.02 mg/kg). However, dexamethasone 1 mg/kg significantly suppressed plasma cortisol and adrenocorticotropic hormone levels compared with anti-CD163 dexamethasone (0.02 mg/kg; p < 0.05). No significant hemodynamic difference existed between groups. The anti-CD163 dexamethasone drug conjugate exhibited a fast plasma clearance, with a half-life of approximately 5-8 minutes.
Conclusion:
Targeted delivery of dexamethasone to macrophages using a humanized CD163 antibody as carrier exhibits anti-inflammatory effects comparable with 50 times higher concentrations of free dexamethasone and does not inhibit endogenous cortisol production. This antibody-drug complex showing similar affinity and specificity for human CD163 is, therefore, a promising drug candidate in this novel type of anti-inflammatory therapy.
Insights
Targeted delivery of dexamethasone to macrophages via an anti-CD163 antibody conjugate reduced pro-inflammatory cytokines without suppressing cortisol. This novel therapy shows promise for treating inflammatory conditions.
Area of Science:
- Immunology
- Pharmacology
- Biotechnology
Background:
- Macrophages are key immune cells producing pro-inflammatory cytokines.
- Glucocorticoids are used to suppress inflammation but have systemic side effects.
- Targeted drug delivery aims to enhance efficacy and reduce side effects.
Purpose of the Study:
- To evaluate targeted delivery of dexamethasone to macrophage receptor CD163.
- To compare its efficacy against systemic glucocorticoid therapy in reducing cytokine response.
- To assess effects on cortisol and adrenocorticotropic hormone levels.
Main Methods:
- Two randomized, placebo-controlled trials in pigs.
- Production and characterization of anti-CD163 antibody conjugated with dexamethasone.
- Administration of treatments prior to lipopolysaccharide infusion.
- Analysis of cytokines, cortisol, and adrenocorticotropic hormone in blood samples.
Main Results:
- Lipopolysaccharide increased cytokine and cortisol levels.
- Targeted dexamethasone and high-dose systemic dexamethasone reduced tumor necrosis factor-α.
- Systemic dexamethasone significantly suppressed cortisol and ACTH compared to targeted therapy.
- Anti-CD163 dexamethasone conjugate showed fast plasma clearance (5-8 min half-life).
Conclusions:
- Targeted dexamethasone delivery to macrophages via CD163 antibody conjugate has anti-inflammatory effects.
- This targeted approach is effective at 50 times lower concentrations than free dexamethasone.
- The antibody-drug complex does not inhibit endogenous cortisol production, making it a promising therapeutic candidate.
